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Archive for the ‘Immuno-Oncology & Genomics’ Category


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Editor-in-Chief: Aviva Lev-Ari, PhD, RN

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How Immunotherapy may sometimes make Cancer worse?

Reporter: Aviva Lev-Ari, PhD, RN

 

A potential explanation is

Advances in Brief Cancer Cell Motility-inhibitory Protein in the Dunning Adenocarcinoma Model1 (2013)

by James L. Mohler , Elaine N. Broskie , Dipak J. Ranparia , Et Al , Contact The Aacr Publications , L. Mohler , Elaine N. Broskie , Dipak J. Ranparia , Yousuf Sharief , William B. Coleman , Cary J. Smith

1 comment

  1. Avatar for Elaine Broskie
    Elaine Broskie2017-04-08 08:22 PM

    Some cancer cells may just be more differentiated and therefore easier to kill with immunotherapy. Simultaneously since they are more differentiated they may be the sort of cells that hold more rogue cancer cells in check. http://citeseerx.ist.psu.edu/viewdoc/summary?doi=10.1.1.326.7968

 

How Immunotherapy may sometimes make Cancer worse?

Warning signs

Kurzrock began asking around, collecting anecdotes about people — and even about laboratory mice — whose tumours had advanced rapidly after treatment with an immunotherapy. Even after collecting examples from several sources, she felt nervous about releasing her results. “We thought, ‘Who’s going to publish this? They’re not going to believe us,’” she says.

Meanwhile, researchers at the Gustave Roussy Institute in Villejuif, France, had stumbled on the same problem. Charles Ferté, an oncologist at the institute, recalls attending a meeting in which several physicians reported bizarre responses to PD-1 treatment. “Some friends and colleagues were saying, ‘I treated lung patients with that drug and the tumour completely exploded in two weeks’,” says Ferté.

Ferté and his colleagues decided to launch a systematic study of tumour growth in their patients. Last November, they published their results: of 131 people who received anti-PD-1 therapies, 9% developed what the investigators called “hyperprogressive” disease, with accelerated tumour growth1. The phenomenon appeared to be more common in people over the age of 65.

On 28 March, Kurzrock and her colleagues published their data from 155 people treated with PD-1 inhibitors and other immunotherapies2. Six of the people had extra copies of MDM2 or MDM4 and 10 had mutations in a gene called EGFR, which is associated with cancer. The team did not see any correlation between age and rapidly worsening disease, but they did notice that tumours grew faster in four of those with the extra MDM2 or MDM4 genes, and in two of the people with EGFR mutations.

SOURCE

6 APRIL 2017 | VOL 544 | NATURE

http://www.nature.com/news/promising-cancer-drugs-may-speed-tumours-in-some-patients-1.21755

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CHI’s Combination Immunotherapy Design Models, February 20-22, 2017, Moscone North Convention Center, San Francisco, CA – part of the 24th International Molecular Medicine Tri-Conference

Reporter: Aviva Lev-Ari, PhD, RN

 

Cambridge Healthtech Institute’s Fifth Annual

Combination Immunotherapy Design Models

Preclinical Approaches and Biomarkers to Bring Combination Therapies to the Clinic

February 20-22, 2017 | Moscone North Convention Center | San Francisco, CA
Part of the 24th International Molecular Medicine Tri-Conference

Despite tremendous progress in our understanding of cancer biology, the majority of novel anticancer therapies fail in clinical trials, which indicates deficiencies in conventional translational approaches. In most cases preclinical data have overpredicted clinical efficacy in oncology. With the rise of immuno-oncology the challenge of in vivo pharmacology was enhanced by the differences in mouse and human immune systems that further damages the predictiveness of preclinical data. The phenomenon of cancer heterogeneity and subsequent drug resistance add another dimension to the preclinical cancer research warranting active work on combination cancer regimens. Better models and approaches are clearly in high and urgent demand and has been worked on by industry and academia scientists. Cambridge Healthtech Institute’s Fifth Annual Translational Models in Oncology and Immuno-Oncology conference is designed to highlight cutting edge advances in in vivo, in vitro and in silico modeling and to facilitate a discussion about effective translational approaches in cancer research.

 

 

MONDAY, FEBRUARY 20

10:30 am Conference Program Registration Open

TRANSLATIONAL IMMUNO-ONCOLOGY

11:50 Chairperson’s Opening Remarks

Terri McClanahan, Ph.D., Executive Director, Molecular Discovery, Biologics, Merck Research Laboratories

12:00 pm KEYNOTE PRESENTATION: Rational Development of Combination Therapies in Immuno-Oncology

Michael Kalos, M.D., CSO, Cancer Immunobiology, Eli Lilly

Treatment of patients with combinations of agents, such as CTLA4 and PD1, has provided additional benefit to patients, along with increased toxicity, highlighting the value for developing combination therapies. In this session, we will discuss preclinical and translational strategies and approaches to support the rational development of more effective combination strategies that lead to increased clinical benefit for patients.

12:30 Biomarker Development for the Era of Combination Cancer Immunotherapy

Terri McClanahan, Ph.D., Executive Director, Molecular Discovery, Biologics, Merck Research Laboratories

Keytruda® (pembrolizumab), a PD-1-specific monoclonal antibody, is approved in the U.S. for advanced melanoma, NSCLC and SCCHN, and is being studied in >30 cancers. Efforts are now underway to extend the benefit of cancer immunotherapy to more patients through the use of anti PD-1-based combination regimens. However, significant challenges remain to identify the best combinations that provide true immune synergy, and to target the right combinations to the right patients who will experience unambiguous clinical benefit. Biomarker and translational research-driven strategies can guide the future state of the field, ultimately allowing for the development of precision medicine approaches to combination cancer immunotherapy.

1:00 Session Break

1:10 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

2:10 Session Break

TRANSLATIONAL IMMUNO-ONCOLOGY (CONT.)

2:30 Chairperson’s Remarks

Christian Gerdes, Ph.D., Head, Pharmacology, Roche Pharma Research & Early Development, Roche

2:40 Immunocompetent Mouse Models as a Tool for Cancer Immunotherapy Pipeline Advancement

Christian Gerdes, Ph.D., Head, Pharmacology, Roche Pharma Research & Early Development, Roche

As immunotherapy gains more and more traction, the need for more predictive preclinical models grows as well. It is widely recognized that immunocompetent mice are used to assess the anti-tumor efficacy of cancer immunotherapies. This presentation will discuss the uses of mouse models and how they can advance drug pipelines.

3:10 Designing and Executing Cancer Immunotherapy Clinical Trials

Pamela N. Munster, M.D., Professor, Medicine, Program Leader, Development Therapeutics, Director, Early Phase Clinical Trials Program, Helen Diller Cancer Center, University of California, San Francisco

A breakdown in immune tumor surveillance plays a crucial role in the development of metastatic cancer. Targeting the programmed death receptor (PD-1) and its ligand (PD-L1) have been major breakthroughs in certain cancers such melanoma, lung and other cancers. However, many cancers, including breast cancers, appear less responsive. We are exploring the roles of tumor lymphocyte infiltration, T cell differential, epigenetic modifiers and the co-operative involvement of other immune pathways to induce responses in immune silent tumors. Translating preclinical findings into early phase clinical studies, we will describe recent advances in how to determine safety, feasibility and efficacy of integrating immunotherapy into targeted therapy and chemotherapy.

3:40 Talimogene Laherparepvec in Combination with Checkpoint Inhibitors: From Bench to Bedside

Pedro J. Beltran, Ph.D., Research Director, Oncology Research, Amgen, Inc.

Checkpoint inhibitors and viral immunotherapy with talimogene laherparepvec have shown significant therapeutic benefit in melanoma patients when used as monotherapies. As these two forms of approved immunotherapy act mostly on different parts of the immunity cycle, studying their combination pre-clinically and clinically informs their future development. We have used 3 syngeneic murine models to study the pharmacodynamic and efficacy changes driven by the combination of talimogene laherparepvec and blockade of CTLA-4 or PD-1/PD-L1. Clinical trials testing these combinations in the clinic are currently ongoing.

4:10 Presentation to be Announced

 

4:25 Sponsored Presentation (Opportunity Available)

4:40 Refreshment Break and Transition to Plenary Session

5:00 Plenary Keynote Session

6:00 Grand Opening Reception in the Exhibit Hall with Poster Viewing

7:30 Close of Day

TUESDAY, FEBRUARY 21

7:30 am Registration Open and Morning Coffee

8:00 Plenary Keynote Session

9:00 Refreshment Break in the Exhibit Hall with Poster Viewing

TUMOR MODELS FOR CANCER IMMUNOTHERAPY

10:05 Chairperson’s Remarks

Gavin Thurston, Vice President, Oncology and Angiogenesis Research, Regeneron Pharmaceuticals

10:15 Mouse Models to Test Human Cancer Immuno-Therapeutics

Gavin Thurston, Vice President, Oncology and Angiogenesis Research, Regeneron Pharmaceuticals

Preclinical in vivo tumor models are essential to test anti-tumor activity and side-effect profiles of novel immunotherapeutics. However, antibody-based therapies often do not cross-react with the corresponding murine targets, making such tests difficult. We have utilized Regeneron’s capabilities in murine genetic engineering to develop several approaches of combining functional immune cells with preclinical tumor models. We have used these approaches for preclinical testing of both checkpoint inhibiting antibodies and T cell-engaging bispecific antibodies.

10:45 Characterization of Molecular and Cellular Properties of Murine Syngeneic Models to Aid Model Selection and Biomarker Discovery for Immune-Oncology Programs

Wenyan Zhong, Ph.D., Senior Principal Scientist, Oncology R&D Group, Pfizer

Preclinical in vivo models for most immuno-oncology (IO) programs require the use of immunocompetent mice bearing syngeneic tumors. To facilitate model selection for use in preclinical efficacy studies, we characterized a panel of mouse tumor cell lines and syngeneic tumor tissues. In this talk, we will discuss molecular and cellular properties of these models.

11:15 Case Study: Blockade of Phosphatidylserine-Mediated Tumor Immune Suppression to Enhance Immune Checkpoint Therapies

Michael Gray, Ph.D., Senior Research Scientist, Peregrine Pharmaceuticals

Phosphatidylserine (PS) exposure in tumors induces non-inflammatory signals which contribute to an immunosuppressive environment. Antibody blockade of PS activates immune responses by promoting M1 macrophages, maturation of dendritic cells and inducing adaptive T-cell responses. PS targeting antibodies enhance the anti-tumor activity of checkpoint antibodies in preclinical tumor models.

MIBioresearch11:45 Methods and Models for Preclinical Immuno-Oncology

Dylan Daniel, Ph.D., Director, Scientific Development, MI Bioresearch

MI Bioresearch has characterized an array of syngeneic immuno-oncology models to support in vivo pharmacology drug discovery. Our characterization includes comprehensive lymphoid and myeloid flow cytometry immune profiling, and model responses to checkpoint inhibitors and focal beam radiotherapy combinations.

12:00 pm Exemplar_GeneticsGenetically Engineered Miniswine Models of Cancer

John Swart, Ph.D., President, Exemplar Genetics

Current preclinical models of cancer fail to accurately recapitulate human disease and do not effectively translated to the clinic. Recently, Exemplar Genetics has developed a genetically engineered miniature swine model that contains a conditional KRAS mutation on the background of TP53-targeted pigs, the ExeGen® TP53+/R167H& KRAS+/G12D miniswine model. This model should allow for the inducement of human-like tumors in a tissue specific manner. Initial characterization of induced tumors demonstrates the transformative nature of this model.

12:30 Session Break

 Mitra Biotech12:35 Luncheon Presentation to be Announced

1:25 Refreshment Break in the Exhibit Hall with Poster Viewing

ADVANCING TRANSLATION WITH NOVEL APPROACHES AND INDUSTRY-ACADEMIA PARTNERSHIPS

2:00 Chairperson’s Remarks

Lawrence B. Schook, Ph.D., Gutsgell Professor, Animal Sciences and Radiology, University of Illinois

2:10 Collaboration for Translation: Academic-Industry Partnerships to Explore Novel Opportunities in the Area of Immuno-Oncology

Joseph Dal Porto, Ph.D., Director, Pfizer Center for Therapeutic Innovation

The Center for Therapeutic Innovation (CTI) -San Francisco is a direct partnership between Pfizer and leading academic institutions, including UC San Francisco, UC San Diego, Stanford University and others, to establish open collaborations designed to rapidly identify targets and develop therapeutic NMEs. The long-term goal is to substantially reduce the time required to translate promising bio-medical research into new medications and therapies. Most recently, CTI has joined with academic oncology and immunology researchers to understand the translatability of emerging targets in the Immuno-Oncology therapeutic arena.

2:40 An Example of a Collaboration between Industry and Academia for Testing Combination Therapies in Preclinical Patient-Derived Xenograft Models of Glioblastoma

Anderson Clark, Ph.D., Director, Translational in vivo Pharmacology, Oncology, EMD Serono Research & Development Institute

John De Groot, Associate Professor, Chair Ad Interim, Neuro-Oncology, The University of Texas MD Anderson Cancer Center

The use of patient-derived xenograft (PDX) models of cancer has increased over the past decade, both in industry and academia, providing preclinical data to support both drug development and basic oncology research.

3:20 The Oncopig Cancer Model (OCM): A Platform for Transitional, Translational and Transformative Advances in Cancer Research

Lawrence B. Schook, Ph.D., Gutsgell Professor, Animal Sciences and Radiology,

University of Illinois

Mammalian models are integral components of basic, translational, and clinical cancer research. Recently, there have been advances in creating large animal transitional porcine cancer models, for use in preclinical and translational research studies with transformational impact for human clinical trials. Pigs, due to their anatomy, physiology, metabolism, and genetics, provide an ideal investigational transitional platform for human clinical trials and offer a critical pathway to narrow gaps in cancer therapy.

3:40 Presentation to be Announced

 

4:10 Hollywood Oscar Dessert Reception in the Exhibit Hall with Poster Viewing

5:00 Breakout Discussions in the Exhibit Hall

These interactive discussion groups are open to all attendees, speakers, sponsors, & exhibitors. Participants choose a specific breakout discussion group to join. Each group has a moderator to ensure focused discussions around key issues within the topic. This format allows participants to meet potential collaborators, share examples from their work, vet ideas with peers, and be part of a group problem-solving endeavor. The discussions provide an informal exchange of ideas and are not meant to be a corporate or specific product discussion. Pre-registration to sign up for one of the topics will occur a week or two prior to the Event via the App.

Humanized Mouse Models

Gavin Thurston, Vice President, Oncology and Angiogenesis Research, Regeneron Pharmaceuticals

  • Appropriate applications of humanized mouse models in immuno-oncology
  • Limitations of current models
  • Areas of future development

Next Generation Cellular Models

Scott Martin, Senior Scientific Manager, Group Lead, Functional Genomics, Discovery Oncology, Genetech Inc.

  • Cancer cell line profiling
  • Large-scale genomic and drug response screening
  • Future directions

Biomarkers for Cancer Combination Design

Jianda Yuan, M.D., Ph.D., Director, Translational Immuno-Oncology Research, Early Clinical Oncology Development, Merck & Co., Inc.

  • Validation of biomarkers before use in clinical care
  • Using prognostic and predictive biomarkers for enrichment and stratification factors in drug development
  • Challenges and Implementation of biomarkers into clinical practice

6:00 Close of Day

WEDNESDAY, FEBRUARY 22

7:00 am Registration Open

7:00 Breakfast Presentation (Sponsorship Opportunity Available) or Morning Coffee

8:00 Plenary Keynote Session

10:00 Refreshment Break and Poster Competition Winner Announced in the Exhibit Hall

TRANSLATIONAL BIOMARKERS IN CANCER IMMUNOTHERAPY DEVELOPMENT

10:50 Chairperson’s Remarks

Jianda Yuan, M.D., Ph.D., Director, Translational Immuno-Oncology Research, Early Clinical Oncology Development, Merck & Co., Inc.

11:00 Next Generation Biomarkers for the Era of Combination Cancer Immunotherapy

Jianda Yuan, M.D., Ph.D., Director, Translational Immuno-Oncology Research, Early Clinical Oncology Development, Merck & Co., Inc.

Sarah Javaid, Ph.D., Senior Scientist, Discovery Pharmacogenomics, Genetics and Pharmacogenomics, Merck & Co., Inc.

Combination approaches are the keys to improving clinical response. From preclinical immune-oncology mouse models to patients enrolled on clinical trials, novel high throughput technologies enable us to understand the mechanisms underlying the complex interactions between the immune system and cancer, identify predictive biomarkers for the patients who will most likely benefit from current immunotherapies, avoid immune-related adverse events and guide the future combination cancer immunotherapy.

11:30 High-Content Molecular Profiling in Preclinical Immuno-Oncology Research

Ruslan Novosiadly, Senior Research Advisor, Cancer Immunobiology, Biomarkers, Eli Lilly

Recent clinical data have revealed the remarkable potential for T cell modulating agents to induce potent and durable responses in a subset of cancer patients. In this presentation, we discuss molecular approaches, platforms and strategies that enable a broader interrogation of the activity of agents that modulate the activity of tumor-specific T cells as well as examples of data sets generated in preclinical studies that have provided important insights into the biological activity of T cell therapies and support further rational development of this exciting treatment modality.

12:00 pm Utility of Quantifying Circulating Lymphocyte Populations as Pharmacodynamic Biomarkers in Trials of Immune Oncology Therapeutics

Nathan Standifer, Ph.D., Scientist II, Clinical Pharmacology and DMPK, MedImmune

Immune oncology (IO) therapeutics are directed at inducing immune responses against tumor cells. Intrinsic to this mechanism of action is the activation of circulating immune cells, which can be most effectively monitored using flow cytometry-based assays. In this presentation, aspects of assay development, validation, implementation and analysis of clinical flow cytometry datasets will be discussed. Results from clinical trials of IO as single agents or in combination with other IO will be shown and strategies for interpretation and post-hoc analyses will be detailed.

12:30 Session Break

Cellecta 12:40 Luncheon Presentation to be Announced

 

1:10 Refreshment Break in the Exhibit Hall and Last Chance for Poster Viewing

CELLULAR MODELS FOR COMBINATION THERAPY DESIGN

1:50 Chairperson’s Remarks

Scott Martin, Senior Scientific Manager, Group Lead, Functional Genomics, Discovery Oncology, Genetech

2:00 Understanding and Predicting Cellular Response through Chemical and Functional Genomic Profiling of Well-Characterized Cancer Cell Lines

Scott Martin, Senior Scientific Manager, Group Lead, Functional Genomics, Discovery Oncology, Genetech

Determining relationships between genomic features and drug sensitivity is central to the concept of personalized medicine and indication selection. Many studies have highlighted the value of integrating omics data with drug activity across cell lines to identify predictors of response. Here we extend upon these studies with numerous chemical and genetic perturbations to explore such relationships. Data reveals both known and novel correlations, and was also used to explore best experimental and computational practices.

2:30 Beyond Genomics: Identifying Treatment Options for Refractory Cancer Patients Using Real Time Functional Assays and FDA Approved Drug Combinations

Matthew De Silva, CEO, Founder, Notable Labs

Refractory cancer patients often have resistant disease that does not respond to single agent therapy. Combination strategies are promising, but patient heterogeneity makes clinical trial design difficult. Next generation functional phenotypic assays using a patient’s cancer cells can identify potentially synergistic treatments in a matter of days, but the combinatorial space is often larger than the available cells. In silico models that employ ‘omic data from a patient can prioritize which combinations to test ex vivo. If the agent(s) of choice are approved, physicians can then prescribe them

3:00 Generation of ex vivo Tumor Models from PDX Tumors as a Platform for Clinically Relevant Anticancer Drug Discovery

Geoffrey A. Bartholomeusz, Ph.D., Associate Professor and Director, siRNA Core Facility, Department of Experimental Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center

Monolayer cell cultures platforms inadequately represent the complex tumor microenvironment and drugs identified by these systems have failed when translated into the clinics. Clinically relevant PDX systems are both costly and time consuming. We have developed a clinically relevant ex vivo tumor tissue system derived from a PDX tumor, and preliminary data confirms its potential to serve as a platform for clinically relevant drug discovery in a time and cost effective manner.

3:30 Session Break

CRISPR FOR TUMOR MODELING, INTERNATIONAL INITIATIVES

3:40 Chairperson’s Remarks

Monte Winslow, Ph.D., Assistant Professor, Genetics, Stanford University

3:45 Cancer Modeling with in vivo CRISPR/Cas9 Genome Editing

Monte Winslow, Ph.D., Assistant Professor, Genetics, Stanford University

Conventional genetically engineered mouse models of human cancer have been instrumental in our understanding of all aspects of cancer development. However, these models are much too labor-intensive, expensive, and slow to perform the extensive molecular analyses needed to adequately comprehend this disease. I will discuss our ongoing work to employ CRISPR/Cas9-mediated genome editing to generate cancer models and illuminate gene function during cancer progression within the natural in vivo setting.

4:15 Tailored Pre-Clinical Models with CRISPR-Based Genome Editing

Lukas Edward Dow, Assistant Professor, Medicine, Weill Cornell Medicine

CRISPR/Cas9 genome editing has changed the way we design and execute in vivo experiments. We are using CRISPR-based genome editing in stem cells and in adult mice to generate tailored pre-clinical models. This allows both a deeper understanding of the genetic underpinnings of cancer progression and provides a platform to interrogate new therapeutic strategies in specific genetic contexts, which is key for realizing the potential of personalized medicine.

4:45 The Human Cancer Model Initiative

Louis M. Staudt, M.D., Ph.D., Director, Center for Cancer Genomics, Co-Chief, Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health

The Human Cancer Model Initiative (HCMI) aims to generate 1000 new cancer cell lines directly from patient biopsy material using a variety of technologies, including organoids and conditionally reprogrammed cells. Each cell line will be genomically characterized and clinical diagnostic and therapeutic data will be gathered from the participating patients. The new cell lines and their associated data will be made available to the research community to promote a deeper understanding of cancer and its response or resistance to therapy.

5:15 Close of Conference Program

SOURCE

http://www.triconference.com/Pre-Clinical-Oncology-Models/

From: Marina Filshtinsky <pete@healthtech.com>

Date: Wednesday, December 14, 2016 at 10:00 AM

To: Aviva Lev-Ari <AvivaLev-Ari@alum.berkeley.edu>

Subject: Combination Immunotherapy Design Models

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Researchers at Dana-Farber/Boston Children’s: Differences in wiring of “exhausted” and effective T cells indicate possible gene-editing targets

Reporter: Aviva Lev-Ari, PhD, RN

 

“Exhausted T cells display a variety of functional defects,” says Nicholas Haining, MD, of Dana-Farber/Boston Children’s, senior author of the new paper. “They are paralyzed and don’t have the fire-power to destroy cancer or virally-infected cells. For us, the question in this study was, do exhausted cells represent a distinct type of T cell or are they merely a ‘groggy’ version of functional T cells?”

With chronically infected mice as their model, the researchers used a new technology called ATAC-seq to map the regulatory regions of the genome – the sections of DNA involved in switching genes on and off – in the animals’ exhausted and functional CD8+ T cells. (CD8+ T cells are programmed to identify and eliminate cancerous and infected cells.)

“We found the landscape of regulatory regions to be fundamentally different in exhausted and functional T cells,” Haining says. “There were thousands of instances where a regulatory region appeared in exhausted T cells but not in their functional counterparts, and vice versa. This tells us that the two types of cells use very different wiring diagrams to control their gene activity.”

The researchers then tested whether removing a regulatory stretch of DNA that spurs the production of PD-1 would drive down expression of the protein. Using CRISPR/Cas9 technology, they snipped out that region and indeed, PD-1 expression dropped.

SOURCE

http://www.danafarberbostonchildrens.org/news/research-into-basic-workings-of-immune-system-and-cancer.aspx

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LIVE 9/21 3:20PM to 6:40PM KINASE INHIBITORS FOR CANCER IMMUNOTHERAPY COMBINATIONS & KINASE INHIBITORS FOR AUTOIMMUNE AND INFLAMMATORY DISEASES at CHI’s 14th  Discovery On Target, 9/19 – 9/22/2016, Westin Boston Waterfront, Boston

http://www.discoveryontarget.com/

http://www.discoveryontarget.com/crispr-therapies/

Leaders in Pharmaceutical Business Intelligence (LPBI) Group is a

Media Partner of CHI for CHI’s 14th Annual Discovery on Target taking place September 19 – 22, 2016 in Boston.

In Attendance, streaming LIVE using Social Media

Aviva Lev-Ari, PhD, RN

Editor-in-Chief

http://pharmaceuticalintelligence.com

#BostonDOT16

@BostonDOT

 

KINASE INHIBITORS FOR CANCER IMMUNOTHERAPY COMBINATIONS

3:20 Chairperson’s Opening Remarks

Guido J.R. Zaman, Ph.D., Managing Director & Head of Biology, Netherlands Translational Research Center B.V. (NTRC)

3:25 FEATURED PRESENTATION: Inhibition of PI3K and Tubulin

Doriano_Fabbro

Doriano Fabbro, Ph.D., CSO, PIQUR Therapeutics

The PI3K signaling pathway is frequently activated in tumors. PQR309 is a selective dual inhibitor of PI3K and mTOR (currently in Phase I) in cancer patients. The preclinical pharmacology and toxicology of PQR309 is presented, including its activity in lymphoma preclinical models. In addition, we elucidate structural factors defining the PI3K inhibitory activity and tubulin-binding of PQR309 derivatives.

  • PQR309 & GDC0941 arrest cells i G1/S (typical for PI3K/mTOR Inhibitor)
  • What drives Antiproliferative Activity of BKM120: PI3K or MT or both?
  • BKM120 Binds to beta-Tubulin/alpha -Tubulin Interfere
  • T2R-TTL complex
  • Orientation of BKM120 in PI3K
  • PQR309 – is a brain penetrating, PK and BAV by PO, good metabolic stability
  • PQR309 ANti-proliferative in Lymphoma
  • Clinical efficacy – Now in Phase II

4:05 Design and Development of a Novel PI3K-p110β/δ Inhibitor, KA2237 with Combined Tumor Immunotherapeutic, Growth Inhibition and Anti-Metastatic Activity

Stephen_Shuttleworth

Stephen Shuttleworth, Ph.D., FRSC, CChem, CSO, Karus Therapeutics Ltd.

The design and development of KA2237, a novel and selective inhibitor of PI3K-p110β/δ, will be described. This molecule has clinical potential in the treatment of solid and hematological malignancies, through its direct inhibition of tumor growth and metastatic spread, and through immunotherapeutic mechanisms. Phase I studies for KA2237 are scheduled to commence in Q2 2016 at the MD Anderson Cancer Center.

  • Design & Development of Novel, Oral, selective PI3K enzyme family: CLass I,II, III, IV based upon:
  • Class I IA IB
  • KA2237: DUal PI3K – p110beta/delta-selective inhibitor: CTL, Treg, p1 106 T sell response
  • Molecular signature in the tumor
  • WT p110delta, WT 1 10beta+, Mutant p1 10Beta+, PTEN-null, Ibrutinib-resistance, Growth inhibition; suppression of metastesis (p110beta
  • small molecule combination agents: potential aided by selectivity over p110
  • KA2237: clinical Pi3K-p110beta/delta Inhibitor- ATP -comtetitive
  • Doxorubicin -cytotoxic control
  • KA2237 superior activity to Idelasib
  • KA2237 – suppression of micro-metastasis in 4T1 synergenic model
  • Tumor Growth inhibition Pre-Surgery
  • Tumor Re-Growth Inhibition Post-Surgery
  • metastasis post surgery
  • Tumor-free mice post-surgery
  • CHemistry: IHC -pAKT; IHC – FOxp3+
  • KA2237 inhibits HGF-stimulated 4T1 tumor
  • 2004 – Preclinical develpemnt PI3K is reported
  • 2006 First PI#K is enter Clinical Trials
  • Targeting p1110Beta (PIKeCB) mutations in cancer with KA2237
  • DIscovery of the mutations lead drug discovery
  • KA@@#&: Potential in treatment of B-Cell Lymphom AS IN TARGETING IBRUTINIB RESISTENCE
  • GROWTH INHIBITION IN HEMATOLOGICAL CANCERS TUMOE CELL LINE PANEL
  • KA2237 – differentiated from competing Pi3K is Superior efficacy cf. p110delta
  • Combination: Not histone deacetylase but a tubulin deacetylase – Hsp90 ans Hsp70
  • T cell exhausion: Tumor growth inhibition vs Suppression of lung metastasis
  • Tumor BiologyRationale vs Clinical Agents
  • Oncogenic mutants, solid tumor supression magrophage, combination PD-1, CTLA$
  • FDA -approved kinase inhibitors

Summary

  1. phase I clinical study commenced in pathients with B cell Lymphoma
  2. Potential for treatment of solid and hematological malignancies

4:35 InCELL Pulse: A Novel Cellular Target Engagement Assay Platform for Drug Discovery

Treiber_Daniel

Daniel Treiber, Ph.D., Vice President, KINOMEscan, DiscoverX Corporation

InCELL Pulse is a quantitative and rapid method for measuring cellular target engagement potencies for small molecule inhibitors. InCELL Pulse capitalizes on two novel DiscoverX technologies, Enzyme Fragment Complementation (EFC) and Pulse Denaturation, which overcome the limitations of related target engagement methods. Examples across multiple target classes will be described.

  • InCELL Pulse – cellular Target ENgagement Assays
  • cellular thermal stabilization-based approach
  • simple, rapid and generig cellular alternative to CETSa
  • Thermal melting Curves vs Isothermal Inhibitor EC50 curves
  • Pulse Denaturation compound binding, or not binding
  • ABL1 Tyrosine Kinase – dose response curve – allosteric Inhibitor
  • MTH1 Hydrolase: InCELL Pulseassay validated for multiple substrate-competitive inhibitors
  • Validated InCELL Pulse Assays for Diverse Kinases
  • Kinase targets; BRAF, MEC1

Summary

  1. validation across proteins

TTP Labtech4:50 Potential Application of Fluorescence Lifetime Assays to Enable Robust, Rapid Protein Binding Assays

Wylie_Paul

Paul Wylie, Ph.D., Head, Applications, TTP Labtech

Current methods to screen protein binding interactions often have limitations due to the reliance on antibodies, but also interference from fluorescent molecules. Fluorescence lifetime has the potential to overcome these problems through directly labelled proteins and lifetime measurements that are independent of total fluorescence intensity.

  • Protein binding as a target class
  • protein-protein interactions (PPIs)
  1. FRET/HTRF
  2. FP
  3. AlphaScreen

What new in FLT?

  • long lifetime fluorophores, economical reagent platform
  • directly labelled reagents – no antibodies
  • independent of total intensity – reduced interference
  • robustness screen vs nuisance screen – caspase-3
  • productive; reduction false positives: FRET
  • protein-binding assays & FLT formats:
  1. protein – small molecule binding – CECR2
  2. protein – peptide binding: long and sholt lifetime
  3. Site-specific labelling vs Non-selective labelling
  4. Toolbox for PoC
  5. Detection reagents
  6. Further develop technology

5:05 Refreshment Break in the Exhibit Hall with Poster Viewing

 

6:40 End of Day

 

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Milestones in Physiology & Discoveries in Medicine and Genomics: Request for Book Review Writing on Amazon.com


physiology-cover-seriese-vol-3individualsaddlebrown-page2

Milestones in Physiology

Discoveries in Medicine, Genomics and Therapeutics

Patient-centric Perspective 

http://www.amazon.com/dp/B019VH97LU 

2015

 

 

Author, Curator and Editor

Larry H Bernstein, MD, FCAP

Chief Scientific Officer

Leaders in Pharmaceutical Business Intelligence

Larry.bernstein@gmail.com

Preface

Introduction 

Chapter 1: Evolution of the Foundation for Diagnostics and Pharmaceuticals Industries

1.1  Outline of Medical Discoveries between 1880 and 1980

1.2 The History of Infectious Diseases and Epidemiology in the late 19th and 20th Century

1.3 The Classification of Microbiota

1.4 Selected Contributions to Chemistry from 1880 to 1980

1.5 The Evolution of Clinical Chemistry in the 20th Century

1.6 Milestones in the Evolution of Diagnostics in the US HealthCare System: 1920s to Pre-Genomics

 

Chapter 2. The search for the evolution of function of proteins, enzymes and metal catalysts in life processes

2.1 The life and work of Allan Wilson
2.2  The  evolution of myoglobin and hemoglobin
2.3  More complexity in proteins evolution
2.4  Life on earth is traced to oxygen binding
2.5  The colors of life function
2.6  The colors of respiration and electron transport
2.7  Highlights of a green evolution

 

Chapter 3. Evolution of New Relationships in Neuroendocrine States
3.1 Pituitary endocrine axis
3.2 Thyroid function
3.3 Sex hormones
3.4 Adrenal Cortex
3.5 Pancreatic Islets
3.6 Parathyroids
3.7 Gastointestinal hormones
3.8 Endocrine action on midbrain
3.9 Neural activity regulating endocrine response

3.10 Genomic Promise for Neurodegenerative Diseases, Dementias, Autism Spectrum, Schizophrenia, and Serious Depression

 

Chapter 4.  Problems of the Circulation, Altitude, and Immunity

4.1 Innervation of Heart and Heart Rate
4.2 Action of hormones on the circulation
4.3 Allogeneic Transfusion Reactions
4.4 Graft-versus Host reaction
4.5 Unique problems of perinatal period
4.6. High altitude sickness
4.7 Deep water adaptation
4.8 Heart-Lung-and Kidney
4.9 Acute Lung Injury

4.10 Reconstruction of Life Processes requires both Genomics and Metabolomics to explain Phenotypes and Phylogenetics

 

Chapter 5. Problems of Diets and Lifestyle Changes

5.1 Anorexia nervosa
5.2 Voluntary and Involuntary S-insufficiency
5.3 Diarrheas – bacterial and nonbacterial
5.4 Gluten-free diets
5.5 Diet and cholesterol
5.6 Diet and Type 2 diabetes mellitus
5.7 Diet and exercise
5.8 Anxiety and quality of Life
5.9 Nutritional Supplements

 

Chapter 6. Advances in Genomics, Therapeutics and Pharmacogenomics

6.1 Natural Products Chemistry

6.2 The Challenge of Antimicrobial Resistance

6.3 Viruses, Vaccines and immunotherapy

6.4 Genomics and Metabolomics Advances in Cancer

6.5 Proteomics – Protein Interaction

6.6 Pharmacogenomics

6.7 Biomarker Guided Therapy

6.8 The Emergence of a Pharmaceutical Industry in the 20th Century: Diagnostics Industry and Drug Development in the Genomics Era: Mid 80s to Present

6.09 The Union of Biomarkers and Drug Development

6.10 Proteomics and Biomarker Discovery

6.11 Epigenomics and Companion Diagnostics

 

Chapter  7

Integration of Physiology, Genomics and Pharmacotherapy

7.1 Richard Lifton, MD, PhD of Yale University and Howard Hughes Medical Institute: Recipient of 2014 Breakthrough Prizes Awarded in Life Sciences for the Discovery of Genes and Biochemical Mechanisms that cause Hypertension

7.2 Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure: Contributions by Roger J. Hajjar, MD

7.3 Diagnostics and Biomarkers: Novel Genomics Industry Trends vs Present Market Conditions and Historical Scientific Leaders Memoirs

7.4 Synthetic Biology: On Advanced Genome Interpretation for Gene Variants and Pathways: What is the Genetic Base of Atherosclerosis and Loss of Arterial Elasticity with Aging

7.5 Diagnosing Diseases & Gene Therapy: Precision Genome Editing and Cost-effective microRNA Profiling

7.6 Imaging Biomarker for Arterial Stiffness: Pathways in Pharmacotherapy for Hypertension and Hypercholesterolemia Management

7.7 Neuroprotective Therapies: Pharmacogenomics vs Psychotropic drugs and Cholinesterase Inhibitors

7.8 Metabolite Identification Combining Genetic and Metabolic Information: Genetic association links unknown metabolites to functionally related genes

7.9 Preserved vs Reduced Ejection Fraction: Available and Needed Therapies

7.10 Biosimilars: Intellectual Property Creation and Protection by Pioneer and by

7.11 Demonstrate Biosimilarity: New FDA Biosimilar Guidelines

 

Chapter 7.  Biopharma Today

8.1 A Great University engaged in Drug Discovery: University of Pittsburgh

8.2 Introduction – The Evolution of Cancer Therapy and Cancer Research: How We Got Here?

8.3 Predicting Tumor Response, Progression, and Time to Recurrence

8.4 Targeting Untargetable Proto-Oncogenes

8.5 Innovation: Drug Discovery, Medical Devices and Digital Health

8.6 Cardiotoxicity and Cardiomyopathy Related to Drugs Adverse Effects

8.7 Nanotechnology and Ocular Drug Delivery: Part I

8.8 Transdermal drug delivery (TDD) system and nanotechnology: Part II

8.9 The Delicate Connection: IDO (Indolamine 2, 3 dehydrogenase) and Cancer Immunology

8.10 Natural Drug Target Discovery and Translational Medicine in Human Microbiome

8.11 From Genomics of Microorganisms to Translational Medicine

8.12 Confined Indolamine 2, 3 dioxygenase (IDO) Controls the Homeostasis of Immune Responses for Good and Bad

 

Chapter 9. BioPharma – Future Trends

9.1 Artificial Intelligence Versus the Scientist: Who Will Win?

9.2 The Vibrant Philly Biotech Scene: Focus on KannaLife Sciences and the Discipline and Potential of Pharmacognosy

9.3 The Vibrant Philly Biotech Scene: Focus on Computer-Aided Drug Design and Gfree Bio, LLC

9.4 Heroes in Medical Research: The Postdoctoral Fellow

9.5 NIH Considers Guidelines for CAR-T therapy: Report from Recombinant DNA Advisory Committee

9.6 1st Pitch Life Science- Philadelphia- What VCs Really Think of your Pitch

9.7 Multiple Lung Cancer Genomic Projects Suggest New Targets, Research Directions for Non-Small Cell Lung Cancer

9.8 Heroes in Medical Research: Green Fluorescent Protein and the Rough Road in Science

9.9 Issues in Personalized Medicine in Cancer: Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing

9.10 The SCID Pig II: Researchers Develop Another SCID Pig, And Another Great Model For Cancer Research

Epilogue

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On its way for an IPO: mRNA platform, Moderna, Immune Oncology is recruiting 100 new Life Scientists in Cambridge, MA

Curator: Aviva Lev-Ari, PhD, RN

 

Deals:

Moderna has now raised $1.9 billion from investors like AstraZeneca – 9% stack [AstraZeneca’s Pascal Soriot helped get that all started with a whopping $240 million upfront in its 2013 deal, which was tied to $180 million in milestones.], with another $230 million on the table from grants. In addition to the financing announcement this morning, Moderna is also unveiling a pact to develop a new Zika vaccine, with BARDA putting up $8 million to get the program started while offering an option on $117 million more to get through a successful development program.

Novel Strategy in Biotech:

in biotech. Instead of grabbing one or two new drugs and setting out to gather proof-of-concept data to help establish its scientific credibility, the company has harvested a huge windfall of cash and built a large organization before even entering the clinic. And it did that without turning to an IPO.

Pipeline include:

  • The deal with AstraZeneca covers new drugs for cardiovascular, metabolic and renal diseases as well as cancer.
  • partners filed a European application to start a Phase I study of AZD8601, an investigational mRNA-based therapy that encodes for vascular endothelial growth factor-A (VEGF-A)
  • Moderna CEO spelled out plans to get the first 6 new drugs in the clinic by the end of 2016.
  • The first human study was arranged for the infectious disease drug mRNA 1440, which began an early stage study in 2015.
  • Moderna built up a range of big preclinical partnerships.
  • CEO Bancel says the number of drugs in development has swelled to 11, with the first set of data slated to be released in 2017.
  • Moderna also plans to add about 10 drugs to the clinic by next summer,

 

SOURCES

UPDATED: Booming Moderna is raising $600M while ramping up manufacturing and clinical studies

$1.9B in: Moderna blueprints $100M facility, plans to double the pipeline after a $474M megaround

http://endpts.com/moderna-blueprints-100m-facility-plans-to-double-the-pipeline-after-a-474m-megaround/?utm_source=Sailthru&utm_medium=email&utm_campaign=Issue:%202016-09-07%20BioPharma%20Dive%20%5Bissue:7155%5D&utm_term=BioPharma%20Dive

 

Moderna Therapeutics Deal with Merck: Are Personalized Vaccines here?

Curator & Reporter: Stephen J. Williams, PhD – August 11, 2016

https://pharmaceuticalintelligence.com/2016/08/11/moderna-therapeutics-deal-with-merck-are-personalized-vaccines-here/

 

at #JPM16 – Moderna Therapeutics turns away an extra $200 million: with AstraZeneca (collaboration) & with Merck ($100 million investment)

Reporter: Aviva Lev-Ari, PhD, RN – January 13, 2016

https://pharmaceuticalintelligence.com/2016/01/13/at-jpm16-moderna-therapeutics-turns-away-an-extra-200-million-with-astrazeneca-collaboration-with-merck-100-million-investment/

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